Processes for the preparation of substituted tetrahydro beta-carbolines

Abstract

Provided herein are improved processes for the synthesis of substituted tetrahydro beta-carboline derivatives. In particular, provided herein are improved processes useful for the preparation of (S)-4-chlorophenyl 6-chloro-1-(4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4- b ]indole-2(9H)-carboxylate. Formula (I)

1 . A process for preparing a compound of Formula (II): 
       
         
           
           
               
               
           
         
         comprising the steps of:
 i) reacting a compound of Formula (IV) with a mixture of a chiral acid in a first solvent mixture: 
 
       
       
         
           
           
               
               
           
         
         and
 ii) recrystallizing the reaction product in a second solvent mixture to provide the compound of Formula (II), wherein
 X is halogen; and 
 R is substituted or unsubstituted C 1  to C 8  alkyl. 
 
 
       
     
     
         2 . The process of  claim 1 , wherein X is chloro. 
     
     
         3 . The process of  claim 1 , wherein R is C 1  to C 8  alkyl substituted with one or more substituents selected from halogen, hydroxyl or C 1  to C 8 alkoxy. 
     
     
         4 . The process of  claim 1 , wherein R is methyl. 
     
     
         5 . The process of  claim 1 , wherein X is chloro and R is methyl. 
     
     
         6 . The process of  claim 1 , wherein the first solvent mixture is a mixture of water and a solvent in a ratio in a range of from about 1 to about 5% volume/volume water:solvent. 
     
     
         7 . The process of  claim 6 , wherein the ratio of the first solvent mixture is in a range of from about 2 to about 5% volume/volume water:solvent. 
     
     
         8 . The process of  claim 7 , wherein the solvent in the first solvent mixture is methanol, ethanol, 1-propanol, 1-butanol or a mixture thereof. 
     
     
         9 . The process of  claim 8 , wherein the solvent in the first solvent mixture is methanol, ethanol or a mixture thereof. 
     
     
         10 . The process of  claim 9 , wherein the solvent in the first solvent mixture is ethanol. 
     
     
         11 . The process of  claim 1 , wherein the solvent in the second solvent mixture is a mixture of water and a solvent, wherein the solvent is iPrOAc, EtOAc, MTBE, MEK, DCM, DCE, toluene, DMA or a mixture thereof. 
     
     
         12 . The process of  claim 11 , wherein the solvent in the second solvent mixture is EtOAc or MEK or a mixture thereof. 
     
     
         13 . The process of  claim 12 , wherein the solvent in the second solvent mixture is MEK. 
     
     
         14 . A process for preparing a compound of Formula (II): 
       
         
           
           
               
               
           
         
         comprising the step of reacting about one equivalent of a compound of Formula (IV) with a chiral acid in a range of from about 0.1 to about 0.5 equivalents in a first solvent mixture comprising a mixture of ethanol and water in a ratio in a range of from about 1 to about 5% volume/volume water:ethanol: 
       
       
         
           
           
               
               
           
         
         to provide the compound of Formula (II), wherein
 X is halogen; and 
 R is substituted or unsubstituted C 1  to C 8  alkyl. 
 
       
     
     
         15 . The process of  claim 14 , wherein the chiral acid is about 0.5 equivalents. 
     
     
         16 . The process of  claim 14 , wherein the ratio of the first solvent mixture is in a range of from about 2 to about 5% volume/volume water:ethanol. 
     
     
         17 . A process for preparing a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof: 
       
         
           
           
               
               
           
         
         comprising the steps of:
 i) reacting a compound of Formula (IV), with a chiral acid in a first solvent mixture: 
 
       
       
         
           
           
               
               
           
         
         
           to provide a compound of Formula (II), wherein
 X is halogen; and 
 R is substituted or unsubstituted C 1  to C 8  alkyl; and 
 
           ii) reacting the compound of Formula (II) with a compound of Formula (III) in the presence of a base and a second solvent mixture comprising water and a solvent: 
         
       
       
         
           
           
               
               
           
         
         
           to provide a compound of Formula (I), wherein 
           X is at each occurrence independently halogen; and 
           R is substituted or unsubstituted C 1  to C 8  alkyl. 
         
       
     
     
         18 . The process of  claim 17 , wherein the first solvent mixture is a mixture of water and a solvent in a ratio in a range of from about 1 to about 5% volume/volume water:solvent. 
     
     
         19 . The process of  claim 18 , wherein the ratio of the first solvent mixture is in a range of from about 2 to about 5% volume/volume water:solvent. 
     
     
         20 . The process of  claim 18 , wherein the solvent in the first solvent mixture is methanol, ethanol, 1-propanol, 1-butanol or a mixture thereof. 
     
     
         21 . The process of  claim 20 , wherein the solvent in the first solvent mixture is methanol, ethanol or a mixture thereof. 
     
     
         22 . The process of  claim 21 , wherein the solvent in the first solvent mixture is ethanol. 
     
     
         23 . The process of  claim 17 , wherein the solvent in the second solvent mixture is iPrOAc, EtOAc, MTBE, MEK, DCM, DCE, toluene, DMA or a mixture thereof. 
     
     
         24 . The process of  claim 23 , wherein the solvent in the second solvent mixture is EtOAc or MEK or a mixture thereof. 
     
     
         25 . The process of  claim 24 , wherein the solvent in the second solvent mixture is MEK. 
     
     
         26 . The process of  claim 1 , wherein a compound of Formula (I) is a compound of Formula (X): 
       
         
           
           
               
               
           
         
       
     
     
         27 . The process of  claim 1 , wherein the compound of Formula (II) is 
       
         
           
           
               
               
           
         
       
     
     
         28 . The process of any of  claim 1 ,  15  or  18 , wherein the chiral acid is N-acetyl-L-phenylalanine, (S)-2-(methoxycarbonylamino)-3-phenylpropanoic acid, (S)-2-(isopropoxycarbonylamino)-3-phenylpropanoic acid, (S)-2-benzamido-3-phenylpropanoic acid, (S)-2-(4-chlorobenzamido)-3-phenylpropanoic acid, (S)-2-(4-methoxybenzamido)-3-phenylpropanoic acid, (S)-3-phenyl-2-(4-(trifluoromethyl)benzamido)propanoic acid, (S)-2-isobutyramido-3-phenylpropanoic acid, (S)-3-phenyl-2-(phenylsulfonamido)propanoic acid, (S)-3-phenyl-2-(4-(trifluoromethyl)phenylsulfonamido)propanoic acid, (S)-2-(4-methoxyphenylsulfonamido)-3-phenylpropanoic acid or (S)-2-(4-methylphenylsulfonamido)-3-phenylpropanoic acid. 
     
     
         29 . The process of any of  claim 1 ,  15  or  18 , wherein the chiral acid is N-acetyl-L-phenylalanine. 
     
     
         30 . The process of  claim 1 , further comprising the step of preparing a compound of Formula (IV) by reacting a compound of Formula (V): 
       
         
           
           
               
               
           
         
         with a solvated base, wherein
 X is halogen, 
 R is substituted or unsubstituted C 1  to C 8  alkyl, and 
 HB is an acid suitable to form a salt with a compound of Formula (V). 
 
       
     
     
         31 . The process of  claim 30 , wherein HB is an acid suitable to form a salt with a compound of Formula (V), such as hydrochloric acid or acetic acid and the solvated base is aqueous ammonium hydroxide in a mixture with ethyl acetate or isopropyl acetate. 
     
     
         32 . The process of  claim 30 , further comprising the step of preparing a compound of Formula (V) by reacting a compound of Formula (VII): 
       
         
           
           
               
               
           
         
         with a compound of Formula (VI): 
       
       
         
           
           
               
               
           
         
         in the presence of a suitable acid in a suitable solvent, wherein
 X is halogen, 
 R is substituted or unsubstituted C 1  to C 8  alkyl, and 
 HB′ is an acid suitable to form a salt with the amino group of a compound of Formula (VII). 
 
       
     
     
         33 . The process of  claim 32 , wherein the suitable acid is hydrochloric acid, the solvent is water or EtOAc and HB′ is hydrochloric acid or acetic acid.